Cannabis Chemistry: Conversion of THC to CBD

CBDecomissioning THC

There are reported methods and patents for converting CBD into THC and for maximizing THC production, but what about the other way around? Could there be a way to convert psychoactive THC into non-psychoactive CBD?

Mechanisms for opening THC.

Looking at the structures of these cannabinoids, one can imagine a plausible mechanism to open up THC’s ether ring to the phenol of CBD. Fortunately, this kind of chemistry has been done before, and there are examples in the literature. Many molecules in nature have similar structures to THC and CBD because they are all part of a larger family of molecules called terpenoids, made from the same biochemical building blocks. So although the conversion of THC to CBD has not actually been reported, to my knowledge, there are conditions in the literature that are directly applicable to this transformation. Specifically, in 2012, the Baran synthesis group at the Scripps Research Institute in La Jolla, CA published a paper in JACS, where they synthesized diverse meroterpenoids from a boron-containing scaffold derived from sclareolide, a fragrant lactone found in sage. Their divergent and scalable synthesis allowed access to a wide variety of structures from nature, and also some synthetic analogues. Among the many reactions that they report, one of them is directly analogous to the conversion of THC to CBD: the conversion of chromazonarol to isozonarol.

Scaling up.

Usually, reactions done on a small scale (15 mg of starting material was used) are not directly applicable to an industrial scale without substantial effort. Since it was a final step, they did not need to optimize the reaction to be environmentally friendly or cost effective, as it was not a priority for the broad goals of this project. The conditions that they report (dichloromethane as solvent, -78 degree C temperature, BCl3 as a Lewis acid, 2,6-di-tert-butyl-4-methylpyridine as a bulky, more selective base), might not be directly scalable, especially for those with limited experience in synthetic chemistry.

Semisynthesis.

The field of natural product synthesis specializes in these types of transformations, to be able to convert one structure to another in order to access a natural product target either from simple commodity chemicals (total synthesis) or another natural product (semisynthesis). The conversion of THC to CBD would be classified as semisynthesis, since the starting material is another natural product – THC. Semisyntheses can have an advantage that the starting material is often similar in structure to the product, thus requiring fewer steps. However, some molecular targets cannot easily be accessed by semisynthesis, but their unique structure can be made from scratch, essentially, using organic chemistry methods to construct the scaffolds from chemical feedstocks. Both total synthesis and semisynthesis are used industrially for different purposes, and both strategies incorporate the same organic chemistry principles when designing a route.

The thought process.

As an important and necessary part of synthesis, reaction conditions are optimized using small amounts before scaling up; hypothesis-driven trial-and-error, or in some cases, high-throughput screening can be used to develop a more robust and ideal process. All factors of this reaction have the potential to be changed: the solvent, the Lewis acid, and the base. I would recommend, first, for a chemist to do this reaction with THC, using the same scale, reagents, and conditions as those in the paper. This would require access to a fume hood, to avoid exposure to the toxic reagents. After getting a sense of this, for example find out: what is the yield of CBD? How much recovered THC? Is any of the tetra substituted olefin formed? Then, the reaction conditions can be altered (time, temperature, equivalents) to increase yield, and a different solvent, Lewis acid, or base can be swapped to reduce toxicity and cost. This reaction optimization process may sound complex, and will definitely not be an easy problem to solve, but I know from experience, from a chemistry standpoint, this problem is solvable. With careful observation, organic chemistry intuition, and perseverance, there is no reason we cannot develop a method for converting THC into CBD, essentially “de-commissioning” a Schedule I substance.

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Orion GMP Solutions is a Pharmaceutical Process Engineering firm based out of Denver Colorado. We specialize in the implementation and auditing of GMP Cannabis Manufacturers to assist them in reaching international markets. If you would like to get more information, please send us an email at info@oriongmp.com.

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Purification methods: Cannabinoid Recrystallization

Growing Crystals.

One pretty reliable recrystallization technique involves a mixed solvent system. For this, you will need two solvents of different strength: one that dissolves the molecules easily (Ethyl Acetate) and another that the molecules are mostly insoluble in (Pentane).

Experiment at a small scale.

A good working sample size is around 20-200 mg, and a 20 mL dram vial with a screwcap, or a small round bottom flask with a stopper are ideal. To the evaporated solid sample in the vial, a few mL of pentane are added and then broken up with a stirring rod or metal spatula, ideally sonicated, to produce a fine suspension of the solid. Then, with stirring and/or sonicating, Ethyl Acetate was added one drop at a time until the cloudiness dissipates to a clear, transparent solution. Let the vial sit at room temperature in an undisturbed ventilated area overnight, loosely capped, allowing a slow evaporation to occur. If crystals form in the next few days, they can be collected and washed with cold pentane.

The Layering Method.

If the evaporation leaves behind more of a residue, you can try a layering method. Re-dissolve the sample in the same way that you did before, but before you cap it, using a pipette, add a few mL of pentane slowly and carefully along the side of the vial to make a distinct layer on top. The crystals will form at this layer. Close the cap tightly this time, and let it sit undisturbed in a freezer for a few days. You can try several different ratios of solvent or temperatures. Once you figure out a method that works, you can try that on a larger scale. If your sample is not pure enough for recrystallization, other isolation methods, such a chromatography, may be necessary beforehand.

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If you’re interested in learning more about recrystallization as a method for purifying your extracts, CannaChemist can help. Contact us at info@oriongmp.com and let us help you.

This content is written and supported by Orion GMP Solutions, a pharmaceutical engineering firm dedicated to international standardization of GMP Cannabis.

Cannabis Chromatography

This short article describes the theory and basics of Cannabis Chromatography. CannaChemist has spent quite a bit of time patiently waiting for molecules to separate in chromatography columns used to purify organically synthesised columns, and shares her knowledge here to help you resolve products like THC from CBD rich tinctures.

Chromatography

Chromatography, or “color writing” is a reliable purification and analytical technique that has been used for over a century. In 1897, the American chemist David Talbot Day observed that crude oil turned into bands of color as it seeped upwards through clay. In 1900, the Russian-Italian chemist Mikhail Tsvete used chromatography for the separation of plant pigments such as chlorophyll (green), carotenes (orange), and xanthophylls (yellow). Chromatographic techniques continued to advance substantially, gaining widespread use and winning the 1952 Nobel Prize in Chemistry. Today, there are countless variations of chromatography and even automated instruments that are used by scientists around the world, making all kinds of research more efficient than ever.

It’s all about sand… Silicon Dioxide.

Chromatography is a way of separating and purifying all chemical compounds, not just colors, taking advantage of their differences in properties. More specifically liquid, column, or flash chromatography is a practical and straightforward way to purify a substance from a complex mixture (a natural extract or chemical reaction) by passing it through an inert solid called silica, or silicon dioxide. The different compounds in the mixture will have different degrees of attraction, or stickiness, to the silica, and will pass through it at different rates.

Silicon dioxide, a major constituent of sand, is a network of silicon oxygen bonds. The less polar, or more oily compounds will have less attraction to the polar silica, and come off of the column first. If you had a mixture of THC and CBD, the THC would elute first, since it contains only one alcohol functional group instead of the more polar CBD, which contains two. During this process, the compounds and the silica are dissolved in solvents such as pentane and ethyl acetate. The ratio of ethyl acetate to pentane is increased during the column to elute compounds of increasing polarity. However, this practice can be problematic for greasy nonpolar compounds such as terpenes, and even cannabinoids. If there is not enough attraction between the molecules and the silica, they will all travel quite quickly and elute together, not achieving a good separation.

Reversed Phase Chromatography.

Another form of chromatography, called reversed phase, can be used for these instances. A special hydrocarbon-coated silica is used, which reverses the elution order. Polar solvents such as water and acetonitrile (an organic solvent) are used. The ratio of acetonitrile to water is gradually increased during the run to draw the nonpolar compounds through the stationary phase. THC has greater attraction to the hydrophobic stationary phase, so CBD travels more quickly. If you are looking to remove lesser amounts of THC from a predominantly-CBD sample, reversed phase chromatography, although more expensive than untreated silica, is an ideal technique.

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CBD Recrystallization

Not all solids are created equal. Some molecules can be “more solid” than others. What does this mean? Well, certain kinds of functional groups on the molecule, such as the alcohol, or –OH group, are like little magnets that bind the molecules to each other and make them clump up as a solid. Sucrose, or table sugar, has eight alcohol functional groups. This gives it a crystalline structure and the ability to dissolve in strongly polar solvents such as water. The more –OH groups you have, relative to the overall molecule’s size and other properties, the more solid character the molecule possesses. CBD, or cannabidiol, has two alcohol groups, that is why it is called cannabi-di-ol, meaning “two alcohols”. On the other hand, THC only has one alcohol functional group. The other oxygen is an ether, which is less polar than an alcohol because it is not a hydrogen bond donor. Other portions of the molecule including the terpenoid portion, the benzene ring, and the pentane tail contribute hydrophobic character to the molecule, so even though alcohol groups are present, neither of these cannabinoids are polar enough overall to dissolve well in water, but organic solvents, such as ethanol and methanol will dissolve them more readily.

You might be thinking, a solid is a solid, so why does this matter? It matters for recrystallization. If you added just a small amount of solvent to a mixture of CBD and THC, which would dissolve more easily? The one that is less solid, the THC. If you have a mixture of CBD and THC already dissolved, which one will precipitate more easily? The one that is more solid, the CBD.

THC and CBD are both soluble in alcohol solvents, which is very useful for extraction, but for a recrystallization procedure, a solvent that is a little more selective about what it can dissolve is necessary. A less polar solvent, such as pentane, is needed so at the end of recrystallization the final product can be filtered and collected as a solid. Pentane is just a straight chain consisting of 5 carbons, a very nonpolar solvent. At room temperature, it doesn’t dissolve the cannabinoids well. For recrystallization, temperature control is the trick. When the pentane is near its boiling point (36C), it can actually dissolve the cannabinoids just from that extra input of kinetic energy, and when the solution cools back down to room temperature, which molecule do you think will precipitate first? The CBD!

Articles by CannaChemist are focused on concepts surrounding cannabis chemistry, both regarding the 400+ molecules present in the cannabis plant, and the chemicals typically used for processing and manufacturing cannabis products. These writings are for the purpose of educating and advising those that are striving to achieve GMP standards in the cannabis industry. The intention is that by increasing the knowledge of chemistry principles, you will be able to develop safer, more efficient, reliable, and inventive procedures for your cannabis manufacturing company.

No procedures or ideas developed based on these writings should be attempted without the same safety precautions that would be employed in an industrial or academic setting.

Pure THC and CBD – Green Chemistry

This question was asked in the comments section in cannabis extracts in Reddit – how do you produce pure Δ9 THC that’s appearing in dispensaries??? A fellow named Adam Mueller answered this question, and figured out the sub/supercritical conditions to produce pure Δ9 THC and was issued a patent for it last year.

It is also possible to extract and purify THC to a high concentration using other methods. However, they mostly use solvents that are known to be carcinogenic. CO2, on the other hand, defines a “Green Solvent” – no carcinogenicity, and no waste products that pollute the environment.

Patent: US 2014/0248379 – Process for producing an extract containing THC and CBD from cannabis plant material, and cannabis extracts.

Adam Mueller has several patents describing the extraction of cannabinoids from hemp and drug varieties of cannabis. He represents Delta-9-Pharma GmbH, a company out of Germany. While this information may not be novel to people who are already performing extracts, it is of interest to people who would like to learn about the conditions.

This patent explains the steps from taken from grinding up plant matter, subjecting it to subcritical or supercritical conditions and producing a pure CBD and THC product. An interesting point is that CBD can be converted to THC with the right conditions. Past that, the product is dewaxed and ready for delivery in the activated decarboxylated form.

There are some aspects of the patent that are very useful, but there are downsides to running supercritical CO2, given what we know about the “entourage effect” described by Ethan Russo (1). Cannabinoids alone do not have the highest medicinal benefits as a mixture terpenes and cannabinoids. While this patent describes a way to obtain highly purified CBD and THC, the terpenes end up in a separate fraction. Recombining THC, CBD, and terpenes is not unheard of, but it does require a bit more work.

Raw materials

Mueller’s primary source of raw materials is hemp. This is a logical starting material for countries where it is illegal to cultivate marijuana. For the validation of the patent, he used five different strains that are from French, Hungarian, and Finnish origins. In general, these are industrial hemp varieties that are used for fiber production. The legal requirements for such strains are that they contain no more than 0.3% THC by dried weight of the starting materials.

Sub/Supercritical conditions

Mueller provides a range of conditions that can be used to extract cannabinoids with supercritical CO2. Supercritical conditions range from 31-80℃ and 75-500 bar. Subcritical conditions range from 20-30℃ and 100-350 bar.

Subcritical and supercritical extracts do not come out with the same consistencies. Subcritical extractions preserve more terpenes, while supercritical extractions lose terpenes and increase the waxes. Subcritical extracts have an oil like consistency, have less plant lipids (waxes), and may not need dewaxing, depending on the application and what customers want – it is nearly ready for use in vape pens or to be dabbed. Supercritical extracts have a more solid “crumble” consistency, have more plant lipids, and most certainly require dewaxing in order to be used in vape pens or dabs. Both can be used for edibles.

A follow up point is that both subcritical and supercritical runs can be done on the same starting material. First perform a subcritical run and collect the extract – the extract will still have some terpenes present without being overwhelmed with waxes. Then, the same starting material can be run a second time under supercritical conditions. Running subcritical conditions produces relatively low yields, so to maximize yield (i.e. profitability) one really needs to run supercritical conditions. You may find the extra work of doing two runs is not worthwhile, considering you have to have to do twice the work. There’s always a trade-off somewhere in a process, and this one is for you to decide. For maximum yield, Mueller suggests performing two runs on the same material.

Mueller increases yields by using “entraining agents.” Butane, propane, and ethanol are used in concentrations of 1-10%.

Entraining agents have different properties than supercritical CO2. The critical point (CP) of CO2 is 73.8 bar and 31.5℃; butane has a CP of 38.0 bar and 152℃ (2); propane’s CP is 42.5 bar and 96.7C (3); ethanol’s CP is 63 bar and 241℃. A mathematical description requires computational chemistry to show how the entraining agents interact with the CO2. Suffice it to say, CO2 will be in the supercritical phase and the entraining agents will be in the liquid phase (3), (4). This changes the solvent characteristics of the CO2 and improves extraction yields.

His optimal supercritical conditions range from 45-65℃, 100-350 bar, with his best conditions being 60C and 250 bar. His preferred subcritical conditions range from 20-30℃ and 100-350 bar.

Mueller illustrates the system in figures 1-3. It’s a complicated system that is appropriately named a “CO2 extraction plant.” This system was designed for process scale. The system has three components: the extraction system (figure 1), the CBD cyclization system (figure 2), and the CBD/THC separation system (figure 3).

How CO2 supercritical work – solubility

The extraction starts in the extraction vessel (F1: 1-4). The column(s) is packed with plant material, and the sub/supercritical CO2 begins to strip the plant material of cannabinoids. The cannabinoids are called the solute, and the CO2 is called the solvent. A solvent becomes saturated when it has no more “room” for more solutes to be carried by the solvent.

The cannabinoid saturated solvent then passes into the separating vessels (F1: 5a-5b) in a continuous process. Fresh solvent enters the extraction vessel, dissolves cannabinoids and other phytochemicals, and carries them into the separating vessels. The cannabinoids are the first solutes to pass through the separating vessels, followed by terpenes, and then the undesirable phytochemicals.

The order of the solutes entering the separating vessel (packed with adsorbents) is dependent on how strong of an interaction each molecule has with the adsorbent media. Cannabinoids have the weakest interaction (first out) and the undesirable phytochemicals have the strongest (last out).

The solubility of the different solutes in the solvent depends on both pressure (P) and temperature (T). The general scheme of the system is to go from high P to low P, and high T to low T, in graduated steps. At high P and T have the highest solubility.

As the P and T are reduced, the solubility of certain components is reduced. For example, the extraction vessels and separating vessels run at 60℃ and 250 bar. The terpene/cannabinoid rich solvent is then pumped over to the first collection vessel (10), at 45℃ and 60-75 bar. That reduction in P and T causes the terpenes to fall out of solution. Meanwhile, the cannabinoids are still in solution.

The cannabinoids are then pumped to the next collection vessel (14). T and P are reduced to 20℃ and 50 bar. Under these conditions, the cannabinoids fall out of solution, and are ready for collection.

Dewaxing and decarboxylation

Dewaxing is pretty standard in the industry these days. Unless you run very cold conditions, you’re going to pick up wax in both hydrocarbon and CO2 extractions. To put it simply, cold ethanol is used to dissolve the extract, followed by freezing and filtration. The extract can then be moved on to decarboxylation, which is a well documented process in the industry.

Converting CBD to THC

The second admirable part of this patent is the cyclization reaction of CBD to THC. Molecular/zeolytic sieves and zinc chloride are employed as a catalyst to aid the reaction. The molecular sieves act as a water binding agent, and the zinc chloride acts as a catalyst to reduce the activation energy required for the cyclization reaction.

The conditions are 300 bar and 70℃, and the reaction takes place over a 2 hour time period. The apparatus in figure 2 shows a simple reaction vessel containing the catalysts and extract that are plumbed to a separate collection vessel. The extract is pumped out to the collection vessel by precipitation with 55 bar and 25℃.

Pure Δ9 THC

The final step described in the patent is the separation of CBD, Δ8 THC, and Δ9 THC. This is achieved by using a purification material/media commonly used in separation science – silica. As is described below in the chromatography, silica has a charge to it, that reacts with the molecules that are to be separated/purified from one another. Some molecules have a stronger interaction than others and therefore travel slower through the silica packed column. In this case, Mueller ends up with pure fractions of the three cannabinoids.

The silica used in the patent has an average size of 0.1mm, and is commonly used in separation science. Looking at figure 3, you will see that the CBD/THC mixture starts at the bottom of the column. When the supercritical CO2 is pumped into the system, the mixture travels up the column and begins to separate the mixture.

After the separation column, there are three collection vessels. As with the initial extraction, CBD, Δ8 THC, and Δ9 THC are separated out by precipitation. The precipitation occurs from dropping the P and T in steps from high to low. CBD is precipitated at 70 bar and 50℃. Δ8 THC is precipitated at 60 bar and 30℃, and Δ9 THC is precipitated at 55 bar and 25℃.

Separation of plant phytochemicals, terpenes, and cannabinoids

The first step in this patent produces pure THC/CBD while removing the plant alkaloids, flavonoids, and chlorophyll. It also removes terpenes.

Without good separation/purification, the terpene fraction can be contaminated with plant alkaloids, flavonoids, and chlorophyll. This is one of the inherent downsides to CO2 extractions compared to butane extractions; phytochemical contamination can be reduced in butane extractions by keeping conditions at sub-zero temperatures. In CO2 extractions, it can be reduced by not cranking the extractor into “hyperdrive” conditions.

Although the loss of terpenes is an inherent problem with supercritical CO2, it’s easiest to preserve terpenes by performing a subcritical run followed by supercritical run. This maximizes the yields, but is not explicitly described as the method used in this patent – it only suggests that the materials are extracted a second time.

Adsorbents

The use of adsorbents is illustrated by way of a packed column in figure 1. An adsorbent is a substance that attracts molecules, and the molecules subsequently adhere to the surface. Note that this is not the same as absorbing, where a molecule is taken into the structure of the substance. An adsorbant has a transient interaction with the molecules it attracts, where the molecules stay on the surface. An absorbant actually soaks up a molecule into its pores, rather than just staying on the surface.

Adsorbents are used in this patent to remove undesirable molecules, such as alkaloids, flavonoids, and chlorophyll. The adsorbents attract undesirable molecules. They adhere to the surface under sub and supercritical conditions, temporarily falling out of the supercritical solution, while the terpenes and cannabinoids stay in solution and pass on to the next section of the system. It is a clever way to remove the undesirables, but is relatively common in separations science.

The adsorbents are silica gel, diatomaceous earth, bentonite, bleaching earth, activated carbon, and mixtures of magnesium oxide and alumina zeolitic. Although it’s not explicitly said, there are two ways that the adsorbents can be used. First, you can pack the plant matter on top of a bed of adsorbents. The second method is to have secondary column in-line, downstream of the extraction chamber, that pulls out all undesirables. The second is much more clean and efficient, but requires additional equipment, and at these kinds of pressure ratings, stainless steel is not cheap.

Chromatography

A more subtle point, that may not be immediately apparent, is the application of chromatography. Chromatography is loosely defined as the separation of mixtures. In this case, the mixture to be separated is the undesirable plant phytochemicals and the desirable terpenes/cannabinoids. The main function of chromatography media (i.e. adsorbents and silica) is to allow some molecules to travel through the media faster than others.

When a molecule has a strong interaction with the chromatography/purification media, it travels slower. When a molecule has a weak interaction, or is repelled by the media, it travels faster. Imagine each phytochemical being a molecular magnet. For example THC and CBD are very weak magnets compared to alkaloids, flavonoids, and chlorophyll. In fact, the undesirable molecules are like strong magnets.

The way this works, is that the adsorbents are also like strong magnets, but have the opposite charge of the undesirable phytochemicals. Opposites attract, and the undesirable phytochemicals are strongly attracted to the adsorbent, while the desireable terpenes and cannabinoids have a weak attraction to the adsorbent. The weaker the interaction, the faster the molecules can travel through the media, and vice versa.

Extraction, purification, and resolution in supercritical extractions

Extraction is the first step in any purification scheme. The industry is currently focusing on whole plant extracts, without much purification beyond dewaxing. This patent utilizes purification in the process – this is how CBD, Δ8 THC, and Δ9 THC are separated from each other.

As described above, chromatography is the mechanism of separating molecules. This can be done by columns packed with silica, and other packing materials. In chemistry, the packing materials are called purification media. Whatever packing material is used, the purpose is to slow down some of the molecules in order to separate the ones you want from the ones you don’t want.

You can’t talk about chromatography without talking about resolution. Resolution can be simply defined as the amount of separation of two molecules in a purification process. Depending on what kind of packing materials used, you can separate groups of molecules from one another. Some packing materials work better for some types of molecules, and is a chore to find the right media when starting a new purification scheme.

When you put together the extraction step and follow it with purification steps, you can separate groups of molecules. The choice of using purification is one that is dependent on whether one wants a pure product.

The end product

One really needs to ask themselves how important purity is. The more pure of a product desired, the more effort that is required. Do you really want pure crystalline THC and CBD? If yes, this process may be right for you. If you just want an extract, you may want to consider these steps, but take what information is useful to you.

Again, a process is only useful if it is economically viable. The extra effort spent in making pure products is significant, but is a daily reality in the pharmaceutical industry. A point to consider is that the closer you get to a pure product, the higher the chance of losing your product due to mistakes.

Having spent years in chemical purifications, plenty of solvent and product have been lost to simple, avoidable mistakes. To avoid mistakes, clearly define your process before you begin. Always have a plan and think about what you’re going to do before you execute the plan. Be careful, take your time, take good notes, and always keep the safety of the consumer as your top priority.